Lipoprotein Particle Predictors of Arterial Stiffness after 17 Years of Follow Up: The Malmö Diet and Cancer Study.

BACKGROUND: Central arterial stiffness is a surrogate of cardiovascular risk and predicts cardiovascular mortality. Apolipoprotein B lipoproteins are also established cardiovascular risk factors. It is not known whether specific lipoprotein subclasses measured in the Malmö Diet and Cancer Study and previously shown to be associated with coronary heart disease also predict arterial stiffening after a mean period of 17 years. METHODS: Lipoprotein particle analysis was performed on 2,505 men and women from Malmö, Sweden, from 1991 to 1994, and arterial stiffness was assessed by carotid-femoral pulse wave velocity (c-fPWV) on this same cohort from 2007 to 2012. Associations between c-fPWV and lipoprotein particles were determined with multiple linear regression, controlling for sex, presence of diabetes, waist-to-hip circumference, and smoking status at baseline, as well as heart rate (measured at the carotid artery), mean arterial pressure, antihypertensive and lipid-lowering medications, C-reactive protein (CRP), and age at the time of c-fPWV measurement. RESULTS: The results confirm that triglycerides (TG) and high-density lipoprotein cholesterol (HDL-c) but not low-density lipoprotein cholesterol (LDL-c) predict c-fPWV. We identify a positive predictive association for very small, small, and medium (high risk), but not large LDL particles. There was a negative association for large HDL particles. The relationships between c-fPWV and high-risk LDL particles were unaffected by adjusting for LDL-c or CRP and were only mildly attenuated by adjusting for the homeostatic model for insulin resistance (HOMA-IR). Due to the collinearity of very small, small, and medium LDL particles and dyslipidemia (elevated TG and decreased HDL-c), the observed relationship between c-fPWV and high-risk LDL particles became insignificant after controlling for the concentration of HDL-c, large cholesterol-rich HDL particles, and TG. CONCLUSIONS: The development of central arterial stiffness previously associated with combined dyslipidemia may be mediated in part by LDL particles, particularly the very small-, small-, and medium-sized LDL particles.

A genetic risk score for fasting plasma glucose is independently associated with arterial stiffness: a Mendelian randomization study.

BACKGROUND: Arterial stiffness is known to be associated with a number of clinical conditions including hypertension, diabetes and dyslipidemia, and may predict cardiovascular events and mortality. However, causal links are hard to establish. Results from genome-wide association studies have identified only a few single nucleotide polymorphisms associated with arterial stiffness, the results have been inconsistent between studies and overlap with other clinical conditions is lacking. Our aim was to investigate a potential shared set of risk single nucleotide polymorphisms between relevant cardiometabolic traits and arterial stiffness. METHOD: The study population consisted of 2853 individuals (mean age 72 years, 40% men) from the population-based Malmö Diet and Cancer study, Sweden. Carotid-femoral pulse wave velocity, a marker of arterial stiffness, was measured with Sphygmocor. Mendelian randomization analyses were performed using the two-stage least square regression and multivariate inverse-variance weighted methods. RESULTS: There were positive associations between arterial stiffness and genetic risk scores for type 2 diabetes (ß = 0.03, P = 0.04) and fasting plasma glucose (ß = 0.03, P = 0.03), but not for systolic blood pressure, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides. Multivariate inverse-variance weighted methods confirmed the significant positive association for fasting plasma glucose ß coefficients (P = 0.006), but not for type 2 diabetes ß coefficients (P = 0.88). CONCLUSION: Genetically elevated fasting plasma glucose, but not genetically elevated risk of type 2 diabetes, was associated with arterial stiffness suggesting a causal stiffening effect of glycemia on the arterial wall, independently of type 2 diabetes.

Family history of cardiometabolic diseases and its association with arterial stiffness in the Malmö Diet Cancer cohort.

OBJECTIVE: Arterial stiffening increases with age and is associated with increased cardiovascular risk. Several risk factors have been shown to predict the development of arterial stiffening; however, a positive family history (FH+) of cardiometabolic disease (CMD) and hypertension has not been extensively studied. We hypothesize that FH+ of CMD plays a significant role in the development of arterial stiffening in offspring. METHODS: We used data from the population-based Malmö Diet Cancer study (n = 3056) examined in 1992-1996 and again in 2007-2012. Several variables were analysed, including anthropometrics, carotid-femoral pulse wave velocity and FH+. The association between FH+ of CMD and arterial stiffening in the offspring was analysed with analysis of covariance in SPSS. FH+ was subdivided into three categories: family history for cardiovascular events (FH-CVEs), family history for diabetes mellitus type 2 (FH-DM2) and family history for hypertension (FH-HT). The first analysis of covariance-model was adjusted for age, sex, mean arterial pressure and heart rate; the second model additionally adjusted for self-reported medical history in the offspring. RESULTS: Data indicated that FH-CVE (F = 14.64, P < 0.001), FH-DM2 (F = 18.57, P < 0.001) and FH-HT (F = 13.92, P < 0.001) all significantly increased carotid-femoral pulse wave velocity levels. The results remained when additional adjustment was made for confounders and for self-reported CMD in the index participants, respectively, for FH-CVE (F = 12.47, P < 0.001), FH-DM2 (F = 7.62, P = 0.006) as well as for FH-HT (F = 7.30, P = 0.007). CONCLUSION: These findings indicate that a FH+ of cardiometabolic conditions and hypertension affects arterial stiffness in offspring independently of haemodynamic factors and self-reported CMD in the offspring without sex differences.

Acute phase proteins as prospective risk markers for arterial stiffness: The Malmö Diet and Cancer cohort.

BACKGROUND AND OBJECTIVES: Arterial stiffness plays a significant role in the development and progression of adverse cardiovascular events and all-cause mortality. This observational study aims to explore the relationship between six acute phase proteins namely, ceruloplasmin, alpha-1-antitrypsin, orosomucoid, haptoglobin, complement C3 and C-reactive protein (CRP), and carotid-femoral pulse wave velocity (c-f PWV) in a population-based cohort, and to also explore the effect of low-grade inflammation on the relationship between diabetes and c-f PWV. METHOD: The study consisted of participants from the Malmö Diet and Cancer study with data from baseline examinations (1991-1994) and follow-up examinations (2007-2012). Arterial stiffness was measured at follow-up by determining c-f PWV. After excluding participants with missing data, the total study population included 2338 subjects. General linear models were used to assess the relationship between baseline acute phase proteins and c-f PWV. RESULTS: After adjusting for traditional risk factors the participants in the 4th quartile vs 1st quartile of alpha-1-antitrypsin (geometric mean: 10.32 m/s vs 10.04 m/s) (p<0.05), C3 (10.35 m/s vs 10.06 m/s) (p<0.05) and CRP (10.37 m/s vs 9.96 m/s) (p<0.001) showed significant association with c-f PWV. Diabetes at follow-up was also associated with high c-f PWV, however, this relationship was independent of low grade inflammation. CONCLUSION: Alpha-1-antitrypsin, C3 and CRP are associated with arterial stiffness. The results indicate that low grade inflammation is associated with arterial stiffness in addition to established cardiovascular risk factors.

Arterial Stiffness and Incidence of Diabetes: A Population-Based Cohort Study.

OBJECTIVE: Diabetes is known to be associated with increased arterial stiffness. However, the temporal association between increased carotid-femoral pulse wave velocity (c-f PWV) and diabetes is unclear. The aim of this study is to explore the relationship between arterial stiffness, as determined by c-f PWV, and incidence of diabetes. RESEARCH DESIGN AND METHODS: The study population included participants from the Malmö Diet and Cancer cardiovascular cohort, using measurements from the 2007-2012 reexamination as baseline. Arterial stiffness was evaluated by measuring c-f PWV (SphygmoCor). After excluding participants with prevalent diabetes (according to measurements of fasting glucose, oral glucose tolerance tests, and physician's diagnoses), the final study population consisted of 2,450 individuals (mean age = 71.9 ± 5.6 years). Incidence of diabetes was followed by linkage to local and national diabetes registers. Cox proportional hazards regression was used to assess the incidence of diabetes in relation to the tertiles of c-f PWV, adjusted for potential confounders. RESULTS: During a mean follow-up of 4.43 ± 1.40 years, 68 (2.8%) participants developed diabetes. Crude incidence of diabetes (per 1,000 person-years) was 3.5, 5.7, and 9.5, respectively, for subjects in the first, second, and third tertiles of c-f PWV. After adjustment for potential confounders, the hazard ratio of diabetes was 1.00 (reference), 1.83 (95% CI 0.88-3.8), and 3.24 (95% CI 1.51-6.97), respectively, for the tertiles of c-f PWV (P for trend = 0.002). CONCLUSIONS: Increased c-f PWV is associated with increased incidence of diabetes, independent of other risk factors. These results suggest that increased arterial stiffness is an early risk marker for developing diabetes.

Non-hemodynamic predictors of arterial stiffness after 17 years of follow-up: the Malmö Diet and Cancer study.

BACKGROUND: Arterial stiffness plays a fundamental role in the development of hypertension and is a risk factor for both cardiovascular disease and mortality. The stiffening that occurs with increasing age has, in numerous cross-sectional studies, been shown to be associated with several cardiovascular risk factors. This observational study aims to characterize the predictive and cross-sectional markers focusing on the non-hemodynamic component of arterial stiffness. METHOD: In all, 2679 men and women from Malmö, Sweden, were examined at baseline during 1991-1994, and again at follow-up during 2007-2012 (mean age 72 years, 38% men). Follow-up examination included measurement of arterial stiffness by carotid-femoral pulse wave velocity (c-fPWV), after a mean period of 17 years. The associations between c-fPWV and risk markers were calculated with multiple linear regression. RESULTS: The results indicated that for both sexes, waist circumference (ß = 0.17, P < 0.001), fasting glucose (ß = 0.13, P < 0.001), Homeostatic Model Assessment - Insulin Resistance (ß = 0.10, P < 0.001), triglycerides (ß = 0.10, P < 0.001), and high-density lipoprotein cholesterol (ß = -0.08, P < 0.001) were all predictors of cfPWV adjusted for mean arterial pressure and heart rate, as well as for classical cardiovascular risk factors and drug treatment. There were no associations between baseline or follow-up low-density lipoprotein cholesterol, smoking, or eGFR and c-fPWV. CONCLUSION: The non-hemodynamic cluster of risk markers and predictors of arterial stiffness in a middle-aged population includes abdominal obesity, hyperglycemia, and dyslipidemia, but not smoking and low-density lipoprotein cholesterol. This pattern existed in both sexes.

Adrenomedullin is a marker of carotid plaques and intima-media thickness as well as brachial pulse pressure.

BACKGROUND: Adrenomodulin (ADM) is a peptide hormone secreted in response to cellular strain such as ischemia and is believed to have a beneficial effect on the cardiovascular system. However, the epidemiological relationships between ADM and measurements of haemodynamics, arteriosclerosis and atherosclerosis are not well established. The aim of this study was to investigate the association between the mid-regional part of pro-ADM (MR-proADM) and brachial pulse pressure (PP), carotid intima-media thickness (cIMT) and carotid atherosclerosis. METHOD: This study has a cross-sectional design and includes 4924 individuals (mean age 58 years, 40% men) from Malmö, Sweden, examined between 1991 and 1994. Participants underwent physical examination, measurement of MR-proADM and ultrasound of the carotid arteries. RESULTS: There was a positive association between MR-proADM and brachial PP, cIMT as well as a carotid plaque score. The associations were significant after adjustment for age, sex, BMI, hypertension, diabetes, low-density lipoprotein cholesterol and smoking. CONCLUSION: ADM is positively associated with brachial PP and both carotid IMT and plaques, suggesting a role for ADM in early haemodynamic pathophysiology related to arteriosclerosis and the atherosclerotic plaque development.